3-Substituted-4-hydroxyphenyl-2-piperidylcarbinols

ABSTRACT

3-Substituted-3-hydroxyphenyl-2-piperidylcarbinols are prepared. These compounds are Beta -adrenergic stimulants and are useful in particular as bronchodilators.

United States Patent [191 Kaiser et al.

[ 3-SUBSTITUTED-4-HYDROXYPHENYL-Z- PIPERIDYLCARBINOLS [75] Inventors: Carl Kaiser, Haddon Heights; Joe R.

Wardell, Jr., Willingboro, both of NJ.

[73] Assignee: SmithKline Corporation,

Philadelphia, Pa.

22 Filed: Oct. 19, 1973 21 App]. No.: 408,147

[451 Oct. 7, 1975 [56] References Cited UNITED STATES PATENTS 3,661,917 5/1972 Kaiser et al. 260/556 AR 3,711,545 1/1973 Kaiser et al. 260/293.73

OTHER PUBLICATIONS J. Med. Chem. 10:462-472, (1967), Larsen et al., RS1 J5.

Primary ExaminerSherman D. Winters Attorney, Agent, or Firm-Stuart R. Suter; Richard D. Foggio; William H. Edgerton [57] ABSTRACT 3-Substituted-3-hydroxyphenyl-2-piperidylcarbino1s are prepared. These compounds are B-adrenergic stimulants and are useful in particular as bronchodilators.

10 Claims, No Drawings 3-SUBSTITUTED-4-HYDROXYPHENYL-2- PIPERIDYLCARBINOLS This invention relates to novel 3-substituted-4- hydroxyphenyl-2-piperidylcarbinols which have useful pharmacodynamic activity. More specifically the compounds of this invention have utility as ,B adrcnergic stimulants with relatively greater activity on respiratory smooth muscle than on cardiac muscle. Therefore, the compounds have direct bronchodilator action with minimal cardiac stimulation.

The compounds of this invention are represented by the following structural formula:

lzzml m zmmo OCYH

wherein:

1.) PhCH Cl with both inorganic or organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismcthylenesalicyclic, methanesulfonic, ethanedisulfonic, acctic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, paminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

The compounds of this invention may be present as diastereoisomers and are designated as erythro and threo isomers which may be resolved as d, 1 optical isomers. Unless otherwise specified in the description and accompanying claims, it is intended to include all isomers, whether separated or mixtures thereof.

The compounds of this invention are prepared by a sequence of reactions; one such sequence of reactions is as follows:

CH B317 o m no N yoto PhCH flail V no General methods for the preparation of phenyl pyridyl ketones are known in the art (Sankey and Whiting,

X is RZNCONH RCONH 55 J. H eterocyclic Chem.,9, 1049 1972 These methods R NSO l IH, or RSO CH each R is hydrogen or C C alkyl; R is C C alkyl; and Y is hydrogen or C -C alkyl.

include reacting an arylaldehyde, for example anisylaldehyde, with a picolinic acid or pyridyl lithium to give a carbinol which is oxidized to the ketone. In addition, a Friedel-Craft reaction of anisole and a picolinic acid chloride also gives the ketone. The 4- methoxyphenyl pyridyl ketones are nitrated to give 4- methoxy-3-nitrophenyl pyridyl ketone. Cleavage of the ether group followed by reaction with benzyl chloride and then chemical reduction gives 3-amino-4- benzyloxyphenyl Z-pyridyl ketone. This compound is hydrogenated or the amino group may be reacted with 3 4 appropriate reagents prior to hydrogenation to give Adxantageously. equal doses will be administered 3 to compounds of this invention. The above mentioned ap- 4 times daily with the daily dosage regimen being about propriate reagents include alkylation and acylation rea- 75 mg to about 200 mg. g Such as hy carboxylic Acid ri fr The phannaccutical carrier employed may be, for exsulfamyl chlorides, alkyl formates and alkyl halides. 5 ample, either solid or liquid. exemplary of solid carri- When X is ureido the amino group is reacted with cyaers are lactose, terra alba. sucrose. talc, gelatin, agar. nate ion, an alkyl cyanate or a dialkylcarbamoyl chlopectin, acacia, magnesium stearate. stearic acid and the ride. like. Exemplary of liquid carriers are syrup, peanut oil, Compounds where X is R'SO CH are prepared by a olive oil, water and the like. Similarly the carrier or dilsequence of reactions such as the following. uent can include any time delay material well known to (31C I Y a N CH O C 3 H EN CH3 N The phenyl pyridyl ketone is treated with formaldehyde the art. such as glyceryl monostearate or glyceryl disand hydrochloric acid in the presence of zinc chloride tearate alone or with a wax. to give the chloromethyl compound. Treatment of this A wide variety of pharmaceutical forms can be emcompound with alkyl magnesium sulfinates followed by ployed. Thus, if a solid carrier is used the preparation ether cleavage and reduction gives the desired carbin e abl ted, placed in a hard gelatin capsule in nols. powder or pellet form, or in the form of a troche or loz- Th compounds f hi invention are g d i 3O enge. The amount of solid carrier will vary widely but stimulants which have direct bronchodilator activity Preferably Wlll be about 25 mg to about l lf a llquld with minimal cardiac stimulation. This selective ,B-stim- Carrier ls used, the Preparation will be lh the form of a ulant activity is determined by two standard in vitro syrup emulsloh, soft getallh Capsule sterlle lhjeetilble pharmacological test systems: 1 effect on spontanellquld such as all p v or an aqueous or hohaqueous ous tone of guinea pig tracheal chain preparation as a 35 llquld peh of Partleulal llpplleablllly for lhlra' measurg of fl stimulant (direct relaxant) effect on nasal administration is an aerosol dispensing system way Smooth muscle and (2) effect on spontaneously wherein the active medicament is incorporated with beating right atria of the guinea pig as a measure of Freon or other inert propellant in an aerosol container. B Stimu]am effect on Cardiac muscle Compounds that Such an aerosol system Wlll deliver a metered dose of show selective bronchodilating properties, as the com- 40 abeut 250 h to about 500 admlhlslered Ghee or pounds of this invention do, are active in test (1) at a l tlme as e e Also useful for lhls P p close lower than is required in test (2) thereby resulting 15 hquld folmulatloh m a Plastic squeeze bottlein a positive separation ratio. Results of test l) are reh followlhg example illustrates the Prephlalloh of ported as the dose which produces 50 percent of the s e Compounds havlhg ls'adreherglc sthhulaht maximum possible relaxation (E1350) Test (2) results tivity and should not be construed as a limitation of the are reported as the dose which produces 25 percent of mvehhohthe maximum possible increase in atrial contraction EXAMPLE 1 rate 25) To one mole of butyl lithium (15% in hexane) at A Preferred Compound Of this invention is H 40C under nitrogen is added gradually a solution of m y yph y -p p y which 142 g 0.9 mol) of Z-bromopyridine in 340 ml. of ether. has an so of 12 g/ ml and an zs 0f g/ maintaining the temperature below 40C. After stir- Another preferred compound, oz-(4-hydroXy-3- ring for 15 minutes at this temperature, a solution of methanesulfonylmethylphenyl)-2-piperidylcarbinol, 122 g (0.9 mol) of 4-methoxybenzaldehyde in 250 ml has an 50 of 14 g/ and an ED25 0f g/m of ether is added, with the temperature below 1 5C. In addition, oz-(4-hydroxy-3-ureidophenyl)-2- The reaction mixture is stirred for 40 minutes at this piperidylcarbinol has an ED of 0.83 mcg/ml and an temperature, quenched in 1.5 1 ice water. The solid is filtered and washed with cold ether to give 4- methoxyphenyl-2-pyridylcarbinol, m.p. l62-l 30C.

To a stirred mixture of 76.5 g (0.36 mol) of the above pyridylcarbinol in 900 ml water at is added in portions 70.5 g (0.446 mol) of potassium permanganate. The reaction temperature is maintained at -100C. for one hour, the heat is withdrawn and excess ethyl acetate is added gradually. The mixture is filtered and the 65 filter cake is washed with hot ethyl acetate. The combined ethyl acetate solution is Washed with water, dried and evaporated in vacuo to yield 4-methoxyphenyl 2 pyridyl ketone, mp 96-98C.

ED of 9.4 meg/ml.

The compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets, capsules, injectables or the like, by incorporating the appropriate dose of a compound of formula I, with carriers according to accepted pharmaceutical practices. Preferably a compound or an acid addition salt thereof is administered orally to an animal organism in a tablet or capsule comprising an amount sufficient to produce B-adrenergic stimulant activity. Each dosage unit will contain the active medicament in an amount of about 25 mg to about 50 mg.

To a stirring mixture of 3 ml (48.3 mmol) 71% HNO and 200 ml H SO at -l5C was gradually added 10.0 g (46.9 mmol) of the above ketone. The reaction is maintained at 5 to -8 for 30 minutes, quenched on ice, and neutralized with solid Na CO The solid 4- methoxy-3-nitrophenyl 2-pyridyl ketone is collected, mp l15ll8C.

To a cold solution of 9.4 g (36.4 mmol) of the nitroketone in 40 ml methylene chloride is added slowly with stirring 9.4 ml (25 g) BBR The reaction is stirred without cooling for 1 hour, evaporated in vacuo, and quenched in water. The solid, 4-hydroxy3-nitrophenyl 2-pyridyl ketone, is collected, mp l5560C.

The above phenol (23.2 g, 0.096 mol) is added gradually to a suspension of sodium hydride (2.5 g, 0.11 mol) in 120 ml dimethyl sulfoxide. When hydrogen evolution subsides, benzyl chloride 13.3 g, 0.105 mol) is added and the mixture is heated to 100 for 4 hours. The reaction is quenched in water and extracted with ether. The extracts are washed with water, dried, and evaporated to 4-benzyloxy3nitrophenyl 2-pyridyl ketone which is triturated with ethanol.

To a refluxing mixture of 19.2 g (0.058 mol) of the above nitrophenyl compound and 2 teaspoonsful of Raney nickel in 200 ml ethanol is added over a 15- minute period a solution of 9.6 g of 99% hydrazine hydrate in 30 ml ethanol. The reaction is refluxed one hour, cooled, and evaporated to a residue which is dissolved in ether. The ether solution is treated with decolorizing carbon and evaporated to give 3-amino-4- benzyloxyphenyl 2-pyridyl ketone as an oil, 14.2 g (86%).

EXAMPLE 2 A solution of 10.0 g (32.8 mmol) of 3-amino-4- benzyloxyphenyl 2-pyridyl ketone in 40 ml of 83% acetic acid in water is treated with 6.4 g (0.1 mol) sodium cyanate. The reaction is stirred at room temperature for 1 hour and then at 100 for 15 minutes. Additional sodium cyanate (2-4 g) is added and the solution is stirred until room temperature is obtained. The reaction is quenched with water, and adjusted to pH with 40% NaOH. The product, 4-benzyloxy-3-ureidophenyl Z-pyridyl ketone is collected, mp 1835C.

A solution of 1.73 g (5 mmol) of the above product in ml concentrated HCl and 15 ml glacial acetic acid is heated on a steam bath for 1 hour, 10 mlconcentrated HCl is added and heating is continued for 1 hour. The solution is concentrated in vacuo and the solid residue is recrystallized from methanol-ether. The solid is hydrogenated in 80 ml methanol and ml water with 0.3 g PtO at 60 psi until hydrogen uptake stops. After filtration, the solution is evaporated and the residue is stripped with ether and triturated with acetone to give a-( 4-hydroxy- 3-ureidophenyl )-2-piperidylcarbinol hydrochloride.

Treatment of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone with an equimolar amount of methyl isocyanate in benzene followed by debenzylation and hydrogenation as described in the above procedure gives a-[hydroxy-3-( 3-methylureido )phenyl ]-2-piperidylcarbinol.

EXAMPLE 3 To an ice-cooled solution of 20.0 g (77.5 mmol) 4- methoxy-3-nitrophenyl 2-pyridyl ketone in 100 ml methylene chloride is added 20 m1 BBr over a 10- minute period. Solution is then stirred at room temperature for 1 hour. The reaction is evaporated in vacuo at 50", and excess methanol is gradually added to the residue and the resulting solution is evaporated. The methanol treatment is repeated. The residue is treated with water and NaHcO the solid 4-hydroxy-3- nitrophenyl 2-pyridyl ketone hydrobromide is collected, mp 1579.

A mixture of 0.5 g of the above product and 0.1 g PtO in 50 ml methanol is hydrogenated at 50 psi for 1 hour. The catalyst is removed and 0.1 g 10% Pd on carbon is added and the hydrogenation is repeated. After filtration the solvent is evaporated and the residue is boiled with ethyl acetate and filtered to give a-( 3-aminio-4-hydroxyphenyl )-2-piperidylcarbinol hydrobromide.

EXAMPLE 4 A mixture of 10.0 g (32.8 mmol) of 3-amino-4- benzyloxyphenyl 2-pyridyl ketone and 40 ml of acetic anhydride is heated on a steam bath for one hour. The reaction is concentrated in vacuo to give a residue which is suspended in water and made basic with 10% NaOH. The aqueous phase is extracted with ether and the dried extracts are evaporated to give 3-acetamido-4-benzyloxyphenyl 2-pyridyl ketone.

The ketone is debenzylated and reduced according to the procedure in Example 3 using PtO as catalyst to yield a( 3-acetamido-4-hydroxyphenyl )-2- piperidylcarbinol.

EXAMPLE 5 A mixture of 10.0 g (32.8 mmol) of 3-amino-4- benzyloxyphenyl 2-pyridyl ketone and 200 ml of ethyl formate is refluxed with stirring for 24 hours. The reaction mixture is evaporated and the residue is dissolved in methylene chloride, then is washed with dilute l-lCl and saturated saline solution. The dried organic phase is evaporated to give 4-benzyloxy-3-formamidophenyl 2-pyridyl ketone.

Debenzylation andreduction of this product by hydrogenation over PtO according to the procedure of Example 3 gives oz-( 3-formamido-4-hydroxyphenyl)-2- piperidylcarbinol.

EXAMPLE 6 A solution of 4.7 g (32.8 mmol) of dimethylsulfamyl chloride in 5 ml of dry pyridine is added to 5.0 g (16.4 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone in ml of dry pyridine at 010C. The reaction mixture is stirred in the cold overnight and then poured in water and extracted with ether. The ether extract is washed with water and extracted with dilute aqueous KOH. This basic extract is washed with ether, acidified with hydrochloric acid and extracted with methylene chloride. The dried organic extract is evaporated in vacuo to give 4-benzyloxy-3-dimethylsulfamoylaminophenyl 2-pyridyl ketone. Hydrogenation over PtO according to the procedure of Example 3 gives a-(4-hydroxy-3-dimethylsulfamoylaminophenyl 2-piperidylcarbinol.

EXAMPLE 7 To a stirred solution of 3.8 g (32.8 mmol) of sulfamyl chloride in 60 m1 of dry benzene at 10C is added, in small portions, 10.0 g (32.8 mmol) of 3-amino-4- benzyloxyphenyl 2-pyridyl ketone. The reaction mixture is stirred at l020C for 30 minutes and then extracted with sodium hydroxide. Addition of hydrochloric acid to the basic extracts precipitates the product, 4benzyloxy3-sulfamoylaminophenyl 2-pyridyl ketone, which is hydrogenated according to the procedure of Example 3 to give a-(4-hydroxy-3 -sultamoylaminophenyl)-2-piperidylcarbinolv EXAMPLE 8 An anhydrous benzene solution of 3acetamido-4- benzyloxyphenyl Z-pyridyl ketone is heated at reflux with sodium until a suspension is formedTo this suspension is added sulfuryl chloride in benzene and the resulting mixture is filtered to remove sodium chloride. The filtrate is evaporated to give 4-benzyloxy-3-(N- chlorosulfonylacetamido)phenyl 2-pyridyl ketone.

An equimolar mixture of the above product and methylamine is heated in anhydrous benzene at 50C for four hours, cooled and filtered. The filtrate is treated with dilute HCl and the organic phase is separated and extracted with dilute NaOH. The basic extract is acidified to give 4benzyloxy-3- methylsulfamoylaminophenyl 2-pyridyl ketone which is hydrogenated over PtO by the procedure of Example 3 to give a-( 4-hydroxy-3- methylsulfamoylaminophenyl )-2-piperidylcarbinol.

EXAMPLE 9 A stirred solution of 40 g (0.41 mol) of phosgene in 150 ml of toluene is held at C while a mixture of (52.5 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone and 300 ml of toluene is added slowly. The mixture is refluxed for minutes and then is concentrated to give 4-benzyloxy-3-isocyanatophenyl 2-pyridyl ketone.

A solution of 10 g of the isocyanate in 150 ml of ethanol is refluxed for 2 hours and then concentrated to give 4-benzyloxy-3-carbethoxyaminophenyl 2-pyridyl ketone.

Hydrogenation over PtO as described in Example 3 gives a-(3-carbethoxyamino-4-hydroxyphenyl)-2- piperidylcarbinol.

Substitution of methanol or isopropanol for ethanol in the above procedure gives as final products oz-( 3- carbomethoxyamino-4-hydroxyphenyl)-2- piperidylcarbinol and a-(3-carboisopropoxyamino-4- hydroxyphenyl)-2-piperidylcarbinol.

EXAMPLE l0 Into a mixture of 10.0 g (47 mmol) of 4- methoxyphenyl Z-pyridyl ketone, 3.7 g of formaldehyde, 6.89 g of anhydrous ZnCl and 25 ml of acetic acid is passed gaseous HCl. The reaction is quenched in water, neutralized with solid NaHCO and extracted with ether. The dried extracts are evaporated to give 3-chloromethyl4-methoxyphenyl Z-pyridyl ketone, mp 92-4C.

To a slurry of 2.61 g (0.01 mol) of the above product in methanol is added a solution of 1.2 g (5.5 mmol) of methyl magnesium sulfinate in hot water. The mixture is refluxed for 4 hours and then poured into cold water. The aqueous solution is extracted with chloroform. The dried extracts are evaporated and the residue triturated with ether to give 3-methanesulfonylmethyl-4- methoxyphenyl 2-pyridyl ketone.

A solution of 0.75 g (2.45 mmol) of the above product in 25 ml of 48% HBr is refluxed for 4 hours and then concentrated to a solid residue which is recrystallizcd from methanol-ether to give 4-hydroxy-3- methanesultonylmcthylphenyl 2-pyridyl ketone hydrobromide. mp 230-2C.

A solution of 5 g of the above hydrobromide in aqueous ethanol is hydrogenated over 0.2 g of PtO v The solvent is removed and the resultant oil is treated with methanol-ether to give a-(4-hydroxy-3- methanesulfonylrnethylphenyl)-2-piperidylcarbinol hydrobromide, mp 2245C.

EXAMPLE 1 1 To a boiling solution of 50 g of 4 methoxybenzaldehyde in 50 ml of p-cymeme is added 112 g of 6-methylpicolinic acid. After heating for 3 hours, the reaction is cooled and extracted with 2 N HCl. The acidic extracts are washed with ether, made basic with ammonia and extracted with ether. Concentration of the dried ether extracts gives 4- methoxyphenyl-( 6-methyl-2-pyridyl) carbinol.

A suspension of 10 g of the above carbinol in 200 ml of water is maintained at 20C while 5 g of KMnO is added portionwise as the color is discharged. Excess reagent is destroyed by the addition of ethanol. The MnO is removed by filtration and washed with boiling acetone. The filtrate is concentrated until the product, 4-methoxyphenyl (6-methyl-2-pyridyl) ketone precipitates.

Substitution of 5-n-butylpicolinic acid in the above procedure for 6-methylpicolinic acid gives 4- methoxyphenyl-(5-n-butyl-2-pyridyl)carbinol which is oxidized in the same manner to 4-methoxyphenyl (5-nbutyl-2-pyridyl) ketone.

EXAMPLE l2 4-Methoxyphenyl (6-methyl-2-pyridyl) ketone and 4-methoxyphenyl (5-n-butyl-2-pyridyl) ketone are nitrated, cleaved with BBr treated with benzyl chloride and reduced according to the procedures of EXample l to give 3-amino-4-benzyloxyphenyl (6-methyl-2- pyridyl) ketone and 3-amino-4-benzyloxyphenyl (5-nbutyl-Z-pyridyl) ketone. These compounds are substituted for 3amino-4-benzyloxyphenyl Z-pyridyl ketone in Example 2 to give a-(4-hydroxy-3-ureidophenyl)-6- methyl-2-piperidylcarbinol hydrochloride and a-(4- hydroxy-3-ureidophenyl )-5 -n-butyl2- piperidylcarbinol hydrochloride. The analogous methylureido compounds are prepared as described in Example 2.

EXAMPLE 13 When 4-methoxy-3-nitrophenyl (6-methyl-2-pyridyl) ketone or 4-methoxy-3-nitrophenyl (5-n-butyl-2- pyridyl) ketone are cleaved and reduced by the procedure of Example 3, a-(3-amino-4-hydroxyphenyl)-6- methyl-2-piperidylcarbinol hydrobromide and oc-(3- amino-4-hydroxyphenyl )-5-n-butyl-2-piperidylcarbinol hydrobromide are obtained.

EXAMPLE l4 Substitution of 3-amino-4-benzyloxyphenyl (6-methyl-2-pyridyl) ketone or 3-amino-4-benzyloxyphenyl (5-n-butyl-2-pyridyl) ketone for 3-amino-4- benzyloxyphenyl Z-pyridyl ketone in Examples 4,5,6,7,8 and 9 gives the appropriate following products:

a-( 3-acetamido-4-hydroxyphenyl )-6-methyl-2- piperidylcarbinol a-( 3-acetamido-4-hydroxyphenyl )--n-butyl-2- piperidylcarbinol oz-( 3-formamido-4-hydroxyphenyl )-6-methyl-2- piperidylcarbinol oz-( 3-formamido-4hydroxyphenyl )-5-n-butyl2- piperidylcarbinol oz-( 4-hydroxy-3-dimethysulfamoylaminophenyl )-6- methyl-Z-piperidylcarbinol a-( 4-hydroxy3-dimethysulfamoylaminophenyl )-5-nbutyl-2-piperidylcarbinol a-( 4-hydroxy- 3-sulfamoylaminophenyl )-6-methyl-2- piperidylcarbinol a-( 4-hydroxy-3-sulfamoylaminophenyl )-S-n-butyl-2- piperidylcarbinol a-(4-hydroxy-3-methylsulfamoylaminophenyl)-6- methyl-Z-piperidylcarbinol a-(4-hydroxy-3methylsulfamoylaminophenyl)-5-nbutyl-2-piperidylcarbinol a-( 3-carbethoxyamino-4-hydroxyphenyl)-6-methyl-2- piperidylcarbinol a-( 3-carbethoxyamino-4-hydroxyphenyl )-5-n-butyl-2-' pipcridylcarbinol a-( 3-carbomethoxyamino-4-hydroxyphenyl )-6-methyl- Z-piperidylcarbinol a-( 3-carbometh0xyamino-4-hydroxyphenyl)-5-nbutyl-2-piperidylcarbinol a-( 3-carboisopropoxyamino-4-hydroxyphenyl )-6- methyl-2-piperidylcarbinol a-( 3-carboisopropoxyamino-4-hydroxyphenyl )-5-nbutyl-2-piperidylcarbinol EXAMPLE EXAMPLE l6 ingredients Mg/Tablet 01-(4-Hydroxy-3-urcidophcnyl )-2- l. l 3* ll.3** pipcridylcarbinol hydrochloride Lactose 63 100 Starch 449 9 Magnesium stearate 0.35 0.6

*Equivalent to 1 mg of the free base "Equivalent to 10 mg of the free base A granulation of the above ingredients is compressed into tablets using 7/32 inch diameter punches for the 1 mg tablets and 9/32 inch diameter punches for the 10 mg tablets. Additional strengths such as 0.5, 5, and 20 mg tablets are prepared using appropriate variations in the above formulation.

We claim:

1. A compound of the formula where X is R NCONl-l, RCONH, R N, ROCONH, or

RSO CH each R is hydrogen or C -C alkyl;

R is C -C alkyl; and

Y is hydrogen or C C alkyl, or a non-toxic pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 where Y is hydrogen.

3. A compound as claimed in claim 2 where X is R NCONH.

4. A compound as claimed in claim 2 where X is RCONl-l.

5. A compound as claimed in claim 2 where X is R N.

6. A compound as claimed in claim 2 where X is RO- CONH.

7. A compound as claimed in claim 2 where X is RSO CH 8. A compound as claimed in claim 3 where R is hydrogen, being the compound a-(4-hydroxy-3- ureidophenyl )-2-piperidylcarbinol.

9. A compound as claimed in claim 5 where R is hydrogen, being the compound a-(3-amino-4- hydroxyphenyl)-2-piperidylcarbinol.

10. A compound as claimed in claim 7 where R is methyl, being the compound a-( 4-hydroxy-3- methanesulfonylmethylphenyl)-2-piperidylcarbinol. 

1. A COMPOUND OF THE FORMULA
 2. A compound as claimed in claim 1 where Y is hydrogen.
 3. A compound as claimed in claim 2 where X is R2NCONH.
 4. A compound as claimed in claim 2 where X is RCONH.
 5. A compound as claimed in claim 2 where X is R2N.
 6. A compound as claimed in claim 2 where X is R''OCONH.
 7. A compound as claimed in claim 2 where X is R''SO2CH2.
 8. A compound as claimed in claim 3 where R is hydrogen, being the compound Alpha -(4-hydroxy-3-ureidophenyl)-2-piperidylcarbinol.
 9. A compound as claimed in claim 5 where R is hydrogen, being the compound Alpha -(3-amino-4-hydroxyphenyl)-2-piperidylcarbinol.
 10. A compound as claimed in claim 7 where R'' is methyl, being the compound Alpha -(4-hydroxy-3-methanesulfonylmethylphenyl)-2-piperidylcarbinol. 